The present invention relates to novel spirooxindole derivatives, and pharmaceutically acceptable salts thereof, with an analgesic effect. The compounds of the invention can thus be used in the prevention and treatment of pain. In further aspects, the invention relates to compounds for use in therapy; to processes for preparation of such new compounds; to pharmaceutical compositions containing at least one compound of the invention, or a pharmaceutically acceptable salt thereof, as active ingredient; and to the use of the active compounds in the manufacture of medicaments for the medical use indicated above. The invention also relates to new intermediates for use in the preparation of the novel compounds.
Certain spirooxindole derivatives are known as intermediates in the syntheses of vasopressin receptor ligands from U.S. Pat. No. 5,728,723 (Elf Sanofi). Patent applications WO 9741125 (SKB), WO 9711697 (MSD), WO 9527712 (CEMAF), and WO 9315051 (Elf) also discloses spirooxindoles as synthetic intermediates.
Certain spirooxindole derivatives are known as local anesthetics from Komet and Thio, Journal of Medicinal Chemistry 1976, 19, 892-8. This publication discloses racemic mixtures and biological studies were limited to toxicity (LD50) in mice and local anesthetic activity (rat sciatic nerve blocking) in which test the compounds were found inferior to lidocaine. No analgesic effects of the spirooxindole derivatives are mentioned.
However, there remains a need for new therapeutic agents to treat chronic pain. Chronic pain can be caused by injury to nerves or by a variety of lesions. As of today there is no clear understanding why some, more or less visible injuries may elicit pain. Medical doctors often find even strong analgesics, such as opioids, distressfully inefficacious when the pain state is involving the nervous system itself, peripheral as well as central. These pain states are often referred to as neuropathic pain. As a final resort clinicians often prescribe drugs which are not considered true analgesics but which by trial and error have been found partly useful. Such agents include tricyclic antidepressants, for example amitriptylin, anticonvulsants like carbamazepine and gabapentin, and some local anesthetics and antiarrhythmics, especially mexiletine.
It has surprisingly been found that certain spirooxindole derivatives exhibit good analgesic properties and are particularly effective in the treatment of chronic pain.
It has surprisingly been found that compounds of the Formula I, which are spirooxindole derivatives, are particularly effective analgesic compounds and thereby suitable in the treatment of pain.
In one aspect, the present invention thus relates to compounds of the general Formula I 
or a pharmaceutically acceptable salt thereof, wherein
R1 is
a) H,
b) substituted or unsubstituted C1-C6 alkyl,
c) C1-C6 alkoxy C2-C6 alkyl,
d) C1-C6 alkylthio C2-C6 alkyl,
e) halogenated C1-C6 alkyl,
f) aryl C1-C6 alkyl,
g) C1-C6 alkenyl, or
h) C1-C6 cycloalkyl C1-C2 alkyl;
R2 is
a) H,
b) C1-C6 alkyl,
c) C2-C4 alkynyl,
d) halogen,
e) substituted or unsubstituted carbamoyl,
f) substituted or unsubstituted carbamoyloxy,
g) C1-C6 alkylcarbonyl,
h) C1-C6 alkoxycarbonyl,
i) C1-C6 alkylcarbonyloxy,
j) hydroxy-substituted C1-C6 alkyl,
k) cyano,
l) nitro,
m) amino,
n) halogenated C1-C6 alkyl,
o) halogenated C 1-C6 alkoxy,
p) halogenated C1-C6 alkylthio,
q) C1-C6 alkylsulfinyl,
r) C1-C6 alkylsulfonyl,
s) C1-C4 alkylsulfinylalkyl,
t) C1-C4 alkylsulfonylalkyl,
u) C1-C6 alkylsulfonylamino,
v) halogenated C1-C6 alkylsulfonylamino,
w) halogenated C1-C2 alkylsulfonyloxy,
x) aminosulfonyl,
y) aminosulfonyloxy,
z) aryl,
aa) heteroaryl,
bb) arylcarbonyl,
cc) heteroarylcarbonyl,
dd) arylsulfinyl,
ee) heteroarylsulfinyl,
ff) arylsulfonyl,
gg) heteroarylsulfonyl, in which any aromatic moiety is optionally substituted,
hh) C1-C6 alkylcarbonylamino,
ii) C1-C6 alkoxycarbonylamino,
ii) C1-C6 alkyl-thiocarbonyl,
kk) C1-C6 alkoxy-thiocarbonyl,
ll) formyl, or
mm)alkoxysulfonylamino;
R3 is
a) H,
b) C1-C6 alkyl,
c) halogen,
d) C1-C6 alkoxy,
e) halogenated C1-C4 alkyl,
f) halogenated C1-C6 alkoxy,
g) halogenated C1-C6 alkylthio,
h) C1-C4 alkylsulfinyl,
i) C1-C4 alkylsulfonyl,
j) C1-C4 alkylsulfinyl C1-C6 alkyl,
k) C1-C4 alkylsulfonyl C1-C6 alkyl,
l) C1-C4 alkylsulfonylamino,
m)halogenated C1-C4 alkylsulfonylamino,
n) aminosulfonyl, or
o) aminosulfonyloxy;
R4 is
a) H,
b) C 1-C4 alkyl, or
c) halogen;
R2 and R3 may together with the carbon atoms to which they are attached, form a saturated or unsaturated ring, optionally containing one or more further heteroatoms, and/or optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CF3, OH, cyano, amino, C1-C6alkyl-NHxe2x80x94, (C1-C6 alkyl)2xe2x80x94Nxe2x80x94, CN, NH2SO2, NH2COxe2x80x94, or C1-C6alkyl-COxe2x80x94;
Any amino moiety in R2-R4 can optionally be substituted with one or two C1-C6 alkyl groups which may be part of a ring;
Ar is
a) benzene,
b) pyridine,
c) thiophene,
d) pyrazine,
e) pyrimidine,
f) oxazole,
g) thiazole,
h) pyrrole,
i) pyrazole, or
j) furan;
X is
a) xe2x80x94NHCOxe2x80x94,
b) xe2x80x94CONHxe2x80x94,
c) xe2x80x94NHxe2x80x94SO2xe2x80x94,
d) xe2x80x94SO2NHxe2x80x94,
e) xe2x80x94OCH2xe2x80x94,
f) xe2x80x94NHCH2xe2x80x94, or
g) xe2x80x94NHCOCH2xe2x80x94;
Y is
a) xe2x80x94CH2xe2x80x94,
b) xe2x80x94CH(C1-C6alkyl)xe2x80x94,
c) xe2x80x94C(C1-C6alkyl)2xe2x80x94, or
d) a single bond;
Z is
a) xe2x80x94CH2CH2CH2xe2x80x94,
b) xe2x80x94CH2CH2CH2CH2xe2x80x94,
c) xe2x80x94CHxe2x95x90CHCH2xe2x80x94,
d) xe2x80x94CHxe2x95x90CHCH2CH2xe2x80x94, or
e) xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94;
provided that when X is xe2x80x94NHCOCH2xe2x80x94 then Y cannot be xe2x80x94CH2xe2x80x94; and excluding the racemic compounds wherein Ar is benzene, R2-R4 is hydrogen, X is NHCO, Y is a single bond, Z is xe2x80x94CH2CH2CH2xe2x80x94, and R1 is ethyl or n-propyl.
The pure enantiomers, racemic mixtures and unequal mixtures of two enantiomers are within the scope of the invention. It should be understood that also all the diastereomeric forms possible are within the scope of the invention.
It will also be appreciated by those skilled in the art, although derivatives of compounds of formula I may not possess pharmacological activity as such, they may be administered parenterally or orally and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives, of which the N-oxide is one example, may therefore be described as xe2x80x9cprodrugsxe2x80x9d. All prodrugs of compounds of formula I are included within the scope of the invention.
Depending on the process conditions the final products of the Formula I are obtained either in neutral or salt form. Salt forms include hydrates and other solvates and also crystalline form polymorphs. Both the free base and the salts of these end products are within the scope of the invention.
Acid addition salts of the new compounds may in a manner known per se be transformed into the free base using basic agents such as alkali or by ion exchange. The free base obtained may also form salts with organic or inorganic acids.
In the preparation of acid addition salts, preferably such acids are used which form suitably pharmaceutically acceptable salts. Examples of such acids are hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, aliphatic, alicyclic carboxylic or sulfonic acids, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, pyruvic acid, p-hydroxybenzoic acid, embonic acid, ethanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, alogenbensenesulfonic acid, toluenesulfonic acid or naphthalenesulfonic acid. All crystalline form polymorphs are within the scope of the invention.
Preferred compounds of the invention are those of Formula I wherein
R1 is
a) H,
b) C1-C4 alkyl,
c) C1-C4 alkoxy C1-C4 alkyl,
d) C1-C4 alkylthio C1-C4 alkyl,
e) fluorinated C1-C4 alkyl,
f) aryl C1-C4 alkyl,
g) C1-C4 alkenyl, or
h) cyclopropylmethyl;
R2 is
a) H,
b) C1-C4 alkyl,
C) C2-C3 alkynyl,
d) halogen,
e) substituted or unsubstituted carbamoyl,
f) substituted or unsubstituted carbamoyloxy,
g) C1-C3 alkylcarbonyl,
h) C1-C3 alkoxycarbonyl,
i) C1-C3 alkylcarbonyloxy,
j) hydroxy-substituted C1-C3 alkyl,
k) cyano,
l) fluorinated C1-C3 alkoxy,
m) fluorinated C1-C6 alkylthio,
n) C1-C3 alkylsulfinyl,
o) C1-C3 alkylsulfonyl,
p) C1-C3 alkylsulfinyl C1-C6 alkyl,
q) C1-C4 alkylsulfonyl C1-C6 alkyl,
r) C1-C3 alkylsulfonylamino,
s) halogenated C1-C3 alkylsulfonylamino,
t) sulfamoyl,
u) sulfamoyloxy,
v) aryl,
w) heteroaryl,
x) heteroarylsulfinyl,
y) arylsulfonyl,
z) heteroarylsulfonyl, in which any aromatic moiety is optionally substituted,
aa) C1-C4 alkylcarbonylamino,
bb) C1-C3 alkoxycarbonylamino,
cc) C1-C3 alkyl-thiocarbonyl, or
dd) C1-C3 alkoxy-thiocarbonyl;
R3 is
a) H,
b) C1-C4 alkyl, or
c) halogen;
R4 is
a) H,
b) C1-C4 alkyl, or
c) halogen,
R2 and R4 may together with the carbon atoms to which they are attached, form a saturated or unsaturated ring, optionally containing one or more further heteroatoms, and/or optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CF3, OH, cyano, amino, C1-C6 alkyl-NHxe2x80x94, (C1-C6 alkyl)2xe2x80x94Nxe2x80x94, CN, NH2SO2, NH2COxe2x80x94, or C1-C6 alkyl-COxe2x80x94;
Any amino moiety in R2-R4 can optionally be substituted with one or two C1-C6 alkyl groups which may be part of a ring;
Ar is
a) benzene,
b) pyridine,
c) thiophene,
d) pyrazine,
e) pyrimidine,
f) oxazole,
g) thiazole,
h) pyrrole,
i) pyrazole, or
j) furan;
X is
a) xe2x80x94NHCOxe2x80x94,
b) xe2x80x94CONHxe2x80x94,
c) xe2x80x94NHxe2x80x94SO2xe2x80x94, or
d) xe2x80x94SO2NHxe2x80x94;
Y is
a) xe2x80x94CH2xe2x80x94,
b) xe2x80x94CH(C1-C6alkyl)xe2x80x94,
c) xe2x80x94C(C1-C6alkyl)2xe2x80x94 or
d) a single bond;
Z is
a) xe2x80x94CH2CH2CH2xe2x80x94,
b) xe2x80x94CH2CH2CH2CH2xe2x80x94,
c) xe2x80x94CHxe2x95x90CHCH2xe2x80x94,
d) xe2x80x94CHxe2x95x90CHCH2CH2xe2x80x94, or
e) xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94;
provided that when X is xe2x80x94NHCOCH2xe2x80x94 then Y cannot be xe2x80x94CH2xe2x80x94; and excluding the racemic compounds wherein Ar is benzene, R2-R4 is hydrogen, X is NHCO, Y is a single bond, Z is xe2x80x94CH2CH2CH2xe2x80x94, and R is ethyl or n-propyl.
More preferred compounds of the invention are those of Formula I wherein
R1 is
a) H,
b) C1-C4 alkyl, or
c) C1-C4 alkoxy C1-C4 alkyl;
R2 is
a) H,
b) C1-C4 alkyl,
c) halogen,
d) substituted or unsubstituted carbamoyl,
e) substituted or unsubstituted carbamoyloxy,
f) C1-C2 alkylcarbonyl,
g) C1-C3 alkoxycarbonyl,
h) cyano,
i) fluorinated C1-C2 alkoxy,
j) fluorinated C1-C6 alkylthio,
k) C1-C3 alkylsulfinyl,
l) C1-C3 alkylsulfonyl,
m) C1-C2 alkylsulfonylamino,
n) C1-C3 alkylcarbonylamino, or
o) C1-C3 alkoxycarbonylamino;
R3 is
a) H,
b) C1-C4 alkyl, or
c) halogen;
R4 is
a) H,
b) C1-C4 alkyl, or
c) halogen;
R2 and R3 may together with the carbon atoms to which they are attached, form a saturated or unsaturated ring, optionally containing one or more further heteroatoms, and/or optionally substituted with one or more substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, CF3, OH, cyano, amino, C1-C6 alkyl-NHxe2x80x94, (C1-C6 alkyl)2xe2x80x94Nxe2x80x94, CN, NH2SO2, NH2COxe2x80x94, or C1-C6 alkyl-COxe2x80x94;
Any amino moiety in R2-R4 can optionally be substituted with one or two C1-C6 alkyl groups which may be part of a ring;
Ar is
a) benzene,
b) pyridine,
c) thiophene,
d) pyrazine,
e) pyrimidine,
f) oxazole,
g) thiazole,
h) pyrrole,
i) pyrazole, or
j) furan;
X is
a) xe2x80x94NHCOxe2x80x94,
b) xe2x80x94CONHxe2x80x94,
c) xe2x80x94NHxe2x80x94SO2xe2x80x94, or
d) xe2x80x94SO2NHxe2x80x94;
Y is
a) xe2x80x94CH2xe2x80x94,
b) xe2x80x94CH(C1-C6 alkyl)xe2x80x94,
c) xe2x80x94C(C1-C6alkyl)2xe2x80x94, or
d) a single bond;
Z is
a) xe2x80x94CH2CH2CH2xe2x80x94,
b) xe2x80x94CH2CH2CH2CH2xe2x80x94,
c) xe2x80x94CHxe2x95x90CHCH2xe2x80x94,
d) xe2x80x94CH2CHCH2CH2xe2x80x94, or
e) xe2x80x94CH2CHxe2x95x90CHCH2xe2x80x94;
including the racemic compounds wherein Ar is benzene, R2-R4 is hydrogen, X is NHCO, Y is a single bond, Z is xe2x80x94CH2CH2CH2xe2x80x94, and R is ethyl or n-propyl.
Particularly preferred compounds of the invention are those of Formula I wherein
R1 is H;
R2 is
a) H,
b) C1-C4 alkyl, or
c) halogen;
R3 is
a) H,
b) C1-C4 alkyl, or
c) halogen;
R4 is
a) H,
b) C1-C4 alkyl, or
c) halogen;
Ar is
a) benzene, or
b) pyridine;
X is
a) xe2x80x94NHCOxe2x80x94,
b) xe2x80x94CONHxe2x80x94, or
c) xe2x80x94NHxe2x80x94SO 2xe2x80x94;
Y is a single bond;
Z is
a) CH2CH2CH2xe2x80x94, or
b) xe2x80x94CHxe2x95x90CHCH2xe2x80x94,
excluding the racemic compounds wherein Ar is benzene, R2-R4 is hydrogen, X is NHCO, is a single bond, Z is xe2x80x94CH2CH2CH2xe2x80x94, and R1 is ethyl or n-propyl.
It has furthermore surprisingly been found that the (S)-enantiomers of the compounds of formula I possess a higher analgesic activity than the (R)-enantiomers and are thus preferred for therapeutic use before the latter and the racemic mixtures.
Another aspect of the present invention is therefore the S-enantiomer, referring to the marked spirocarbon, of the compounds of the general Formula I 
or a pharmaceutically acceptable salt thereof, as defined above.
The following definitions shall apply throughout the specification and the appended claims:
The term xe2x80x9cC1-C6 alkylxe2x80x9d denotes a cyclic or linear, straight or branched, substituted or unsubstituted alkyl group having from 1 to 6 carbon atoms. Examples of said alkyl include, but is not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, clohexyl, and cyclopentyl.
The term xe2x80x9cC1-C6 alkoxyxe2x80x9d denotes a group O-alkyl, wherein alkyl is as defined above.
The terms xe2x80x9cC1-C4 alkylxe2x80x9d, xe2x80x9cC1-C3 alkylxe2x80x9d, xe2x80x9cC1-C2 alkylxe2x80x9d have the corresponding meaning as xe2x80x9cC1-C6 alkylxe2x80x9d.
The term xe2x80x9chalogenxe2x80x9d includes fluoro, chloro, bromo and iodo groups.
The term xe2x80x9carylxe2x80x9d denotes a substituted or unsubstituted C6-C14 aromatic hydrocarbon and includes, but is not limited to, benzene, naphtalene, indene, antracene, fenantrene, and fluorene.
The term xe2x80x9csubstitutedxe2x80x9d denotes e.g. an C1-C6 alkyl, C1-C6 alkylaryl or aryl group as defined above which is substituted by one or more alkyl, alkoxy, halogen, amino, thiol, nitro, hydroxy, acyl, cyano or oxo groups.
The term xe2x80x9cheteroatomsxe2x80x9d denotes a nitrogen, oxygen, sulfur, or a phosphorous atom.
Most preferred compounds according to the invention are listed in the following table. The compounds can be in neutral form or in salt form as earlier indicated, for example in hydrochloride form.
5-Fluorospiro[indolin-3,3xe2x80x2-piperidin]-2-one
5-Fluoro-1xe2x80x2-isopropylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
(R)-5-Fluoro-1xe2x80x2-isopropylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
(S)-5-Fluoro-1xe2x80x2-isopropylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
5,7-Difluorospiro[indolin-3,3xe2x80x2-piperidin]-2-one acetate
5 ,7-Difluoro-1xe2x80x2-isopropylspiro[indolin-3 ,3xe2x80x2-piperidin]-2-one
(S)-5,7-Difluoro-1xe2x80x2-isopropylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
5-Dimethylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
5-Methyl-1xe2x80x2-isopropyl-spiro[indolin-3,3xe2x80x2-piperidin]-2-one
6-Methyl-1xe2x80x2isopropyl-spiro[indolin-3,3xe2x80x2-piperidin]-2-one
4-Methylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
4-Methyl-1xe2x80x2-isopropylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
4-Methyl-1xe2x80x2-propylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
7-Fluorospiro[indolin-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-(+)-7-Fluorospiro[indolin-3,3xe2x80x2-piperidin]-2-one
Spiro[indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Ethylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Propyl-spiro[indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Isopropylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Allylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Cyclopropylmethylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Butylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-s-Butylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
(S)-(+)-1xe2x80x2-Propylspiro[indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Propylspiro[4-azaindolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Butylspiro[4-azaindolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-sec-Butylspiro[4-aza-indolin-3,3 xe2x80x2-piperidin]-2-one
1xe2x80x2-Propyl-5-chlorospiro[7-aza-indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Propylspiro[7-azaindolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Propyl-6-methylspiro[7-aza indolin-3,3xe2x80x2-piperidin]-2-one
1xe2x80x2-Propylspiro[isoindolin-3,3xe2x80x2-piperidin]-1-one Hydrochloride
1xe2x80x2-Isopropylspiro[indoline-3,3xe2x80x2-piperidine]hydrochloride
2,3-Dihydro-1H-1xe2x80x2-Propylspiro[thieno[3,2-b]pyrrol-3,3xe2x80x2-piperidin]-2-one
2,3,1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-Hexahydro-1H-spiro[thieno[3,2-b]pyrrol-3,3xe2x80x2-pyridin]-2-one
2,3,1xe2x80x2,2xe2x80x2,3xe2x80x2,6xe2x80x2-Hexahydro-1H-spiro[5,8-diazaindol-3,3xe2x80x2-pyridin]-2-one
1xe2x80x2,2xe2x80x2,3xe2x80x24xe2x80x2-Tetrahydrospiro[indolin-3,3 xe2x80x2-(7H)-azepin]-2-one
1xe2x80x2,2xe2x80x2,3xe2x80x24xe2x80x2-Tetrahydrospiro[7-azaindolin-3,3xe2x80x2-(7H)-azepin)-2-one
1xe2x80x2-Ethyl-1xe2x80x2,2xe2x80x2,3xe2x80x24xe2x80x2-tetrahydrospiro[4-azaindolin-3,3xe2x80x2-(7H)-azepin)-2-one
1xe2x80x2-Propylspiro[indolin-3,3xe2x80x2-piperidin]-2-one 1xe2x80x2-oxide
Also these compounds can be in neutral form or in salt form as earlier indicated.
(S)-5-Chloro-7-fluorospiro[indolin-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-5-Methylspiro[7-azaindoline-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-5,6-Dimethylspiro[7-azaindoline-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-6-Methylspiro[7-azaindoline-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-5-Chlorospiro[7-azaindoline-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-5,7-Difluorospiro[indoline-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-7-Chlorospiro[indoline-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-7-Fluoro-5-methylspiro[indoline-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-5-Methoxyspiro[indoline-3,3xe2x80x2-(1,2,3,6-tetrahydropyridin)]-2-one
(S)-5-Chlorospiro[indoline-3,3xe2x80x2-piperidin]-2-one
The present invention also provides the following processes for the preparation of compounds of the general Formula I. The compounds of the present invention can be prepared by methods known in the art using commercially available, or readily prepared, starting materials. Many useful methods for synthesis of oxindoles are reviewed by G. M. Karp in Org. Prep. Proced. Int. 1993, 25, 481-513, which is incorporated herein by reference.
It is to be understood that certain functional groups may interfere with other reactants or reagents under the reaction conditions and therefore may need temporary protection. The use of protecting groups is described in xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wutz, Wiley-Interscience (1991).
Process A
A process for manufacture of compounds with the general Formula I comprises the following steps:
a) Compounds of Formula IV 
wherein L is a halogen or a trifluoromethylsulfonyloxy group, Ar, R2-R4 are as defined in Formula I, or can be converted into such groups later in the synthesis sequence, is coupled with a compound of the general Formula II, or a corresponding lower alkyl ester, e.g methyl or ethyl ester, 
wherein R1 is as defined for Formula I or is a nitrogen protecting group, e.g. a Boc group, to give a compound of the general Formula VII 
b) The resulting amide of the general Formula VII is then cyclized using Heck reaction conditions with palladium as a catalyst or sometimes under radical generating conditions to give, after optional removal of protecting groups, a compound of the general formula I
When the above formed spiro compound contains a double bond this may be hydrogenated over a metal catalyst to give the corresponding saturated compound, or by other methods well known to those skilled in the art. The product is thereafter deprotected, if necessary, or the cyclized protected intermediate compound may be further reacted with, for example organometallic reagents, to give new compounds of the invention in which an alkyl or alkynyl group is substituted for a bromine or an aryl- or alkylsulfonyloxy group.
Process B
a) Compound of Formula IV 
wherein Ar, R2-R4, Y are as defined in Formula I, and X is xe2x80x94NHCOxe2x80x94 or xe2x80x94NHxe2x80x94SO2 are alkylated with a compound of the general Formula IX 
wherein Z is as defined in Formula I, L is a bromine, iodine, aryl or alkylsulfonyloxy group, e.g. trifluoromethylsulfonyloxy group, A is oxygen or nitrogen, and PG is a suitable protecting group or, when A is nitrogen, equals R1 of Formula I, to give compounds of the general formula XII 
wherein Ar, R2-R4, Y, and Z are as defined in Formula I, X is xe2x80x94NHCOxe2x80x94, or xe2x80x94NHxe2x80x94SO2xe2x80x94, A is oxygen or nitrogen and PG is a suitable protecting group or, when A is nitrogen, equals R1 of Formula I.
b) An optional transformation step is performed when A is oxygen, wherein the oxygen function is converted into the corresponding amino function by methods well known in the art. One suitable way of accomplishing this conversion is to remove the protecting group to generate the corresponding primary alcohol, which is thereafter converted into a suitable leaving groups, e.g. a tosylate group. The leaving group is thereafter displaced by a suitable amino nucleophile to give a compound of the general formula XII, wherein A is nitrogen.
c) Compounds of the general formula XII can thereafter and after optional removal of protecting groups be cyclized to the Spiro system to give compounds of the formula I under standard Mannich conditions.
Process C
a) Compounds of the general Formula III 
wherein Ar, R1-R4 are as defined in Formula I or R1 is a benzylic protecting group, are oxidised into compounds of the general Formula VI, 
wherein Ar, R1-R4 are as defined in Formula I or R1 is a benzylic protecting group, as is described in Kornet and Thio, Journal of Medicinal Chemistry 1976, 19, 892-8 or as referred to in the previously mentioned review by Karp.
c) Compounds of the general Formula VI are thereafter cyclized under standard Mannich reaction conditions to give a compound of the general Formula I.
Process D
a) Compounds of the general Formula V 
wherein Ar, R2-R4, X and Y are as defined in Formula I and PG is an amino protecting group, is ring-closed using a ruthenium or molybdene complex as a catalyst under standard reaction conditions to give compounds of the general formula VIII 
This metathesis reaction is described in more detail in the review by Grubbs, R. H. and Chang, S. Tetrahedron 1998, 54, 4413-50.
The intermediate V may be prepared by methods known to the one skilled in the art, for example by alkylation of the intermediate IV with e.g. allyl bromide followed by a Mannich reaction with a secondary amine to give a compound of the general formula Va, as is schematically shown below. 
In process B and C the amino protecting group used is preferably an easily removable group, for example groups belonging to the arylmethyl class which can be readily removed by hydrogenolysis, thus releasing the secondary amine of formula I (R1=H). Said compound can be converted to a tertiary amine, by alkylating methods well known in the art. Other suitable protective groups that are described in the organic chemical literature is, for example, an allyl carbamate or a 4-methoxybenzyl group.
Many interconversions of the R2 and R3 groups are also evident to one skilled in the art.
Compounds of the general formula I prepared in this way are racemic. As is well known in the art resolution of the two enantiomers can be conveniently achieved by classical crystallization methods by using a chiral acid such as L- or D-ditoluoyltartaric acid or (+) or (xe2x88x92)-1-camphorsulfonic acid in a suitable solvent such as acetone, water, alcohol, ethyl acetate or their mixture. Another method to achieve the same goal is to separate the enantiomers by chromatography on a chiral column such as Chiralcel OD or Kromasil TBB which are commercially available. A further well known means to obtain pure enantiomers is by preparing a derivative of a racemic intermediate, for example an amide of a secondary amine, with an enantiomerically pure acid and then separating the so formed diastereomers by crystallization or by chromatography.
In a further aspect, the present invention relates to compounds of the formula I for use in therapy, in particular for use in the treatment of pain. The invention also provides the use of a compound of the formula I in the manufacture of a medicament for the treatment of pain.
The novel compounds of the present invention are useful in therapy, especially for the treatment and/or prophylaxis of pain of widely different origins and causes and include acute as well as chronic pain states. Examples are pain caused by chemical, mechanical, radiation, thermal, infectious or inflammatory tissue trauma or cancer, postoperative pain, headache and migraine, various arthritic and inflammatory conditions such as osteo and rheumatoid arthritis, myofascial and low back pain.
Also neuropathic conditions of central or peripheral origin can be treated or prevented with the compounds of the invention . Examples of these pain conditions are trigeminal neuralgia, postherpetic neuralgia (PHN), diabetic mono/poly neuropathy, nerve trauma, spinal cord injury, central post stroke, multiple sclerosis and Parkinson""s disease. Other pain states of visceral origin such as caused by ulcer, dysmenorrhea, endometriosis, IBS, dyspepsia etc. can also be treated or prevented with the compounds of the invention. The compounds of the invention are useful as therapeutic agents in disease states with inappropriate neuronal activity or in neuroprotection for example as anticonvulsants in epilepsy, in the treatment of itch, tinnitus, Parkinson""s disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Alzheimer, stroke, cerebral ischaemia, traumatic brain injury, Huntingdon""s chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia and narcolepsy), tics (e.g. Tourette""s syndrome), and muscular rigidity (spasticity).
A primary aim of the invention is to use compounds of the formula I for oral treatment of neuropathic or central pain states.
The compounds of the invention are also useful for treatment of effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines.
In a further aspect the invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt or solvate, thereof as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression.
The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, the dosages will be in the range of 0.1 to 1000 mg per day of active substance.
In yet a further aspect, the invention relates to pharmaceutical compositions containing at least one compound of the present invention, or a pharmaceutically acceptable salt thereof, as active ingredient.
For clinical use, the compounds of the invention are formulated into pharmaceutical formulations for oral, intravenous, subcutaneous, tracheal, bronchial, intranasal, pulmonary, transdermal, buccal, rectal, parenteral or other mode of administration. The pharmaceutical formulation contains a compound of the invention in combination with one or more pharmaceutically acceptable ingredients. The carrier may be in the form of a solid, semi-solid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the invention. Usually the amount of active compounds is between 0.1-95% by weight of the preparation.
In the preparation of pharmaceutical formulations containing a compound of the present invention the compound selected may be mixed with solid, powdered ingredients, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture may then be processed into granules or pressed into tablets.
Soft gelatine capsules may be prepared with capsules containing a mixture of the active compound or compounds of the invention, vegetable oil, fat, or other suitable vehicle for soft gelatine capsules. Hard gelatine capsules may contain granules of the active compound. Hard gelatine capsules may also contain the active compound in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, cornstarch, amylopectin, cellulose derivatives or gelatine.
Dosage units for rectal administration may be prepared (i) in the form of suppositories which contain the active substance mixed with a neutral fat base; (ii) in the form of a gelatine rectal capsule which contains the active substance in a mixture with a vegetable oil, paraffin oil or other suitable vehicle for gelatine rectal capsules; (iii) in the form of a ready-made micro enema; or (iv) in the form of a dry micro enema formulation to be reconstituted in a suitable solvent just prior to administration.
Liquid preparations may be prepared in the form of syrups or suspensions, e.g. solutions or suspensions containing the active ingredient and the remainder consisting, for example, of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations may contain coloring agents, flavouring agents, preservatives, saccharine and carboxymethyl cellulose or other thickening agents. Liquid preparations may also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.
Solutions for parenteral administration may be prepared as a solution of a compound of the invention in a pharmaceutically acceptable solvent. These solutions may also contain stabilizing ingredients, preservatives and/or buffering ingredients. Solutions for parenteral administration may also be prepared as a dry preparation to be reconstituted with a suitable to solvent before use.
The typical daily dose of the active substance varies within a wide range and will depend on various factors such as for example the individual requirement of each patient, the route of administration and the disease. In general, oral and parenteral dosages will be in the range of 0.1 to 1000 mg per day of active substance.
The compounds according to the present invention can also be used in formulations, together or in combination for simultaneous, separate or sequential use, with other active ingredients, such as
a) opioid analgesics, for example morphine, ketobemidone or fentanyl
b) analgesics of the NSAED class, for example ibuprofene, selecoxib or acetylsalicylic acid
c) amino acids such as gabapentin or pregabalin
d) analgesic adjuvants such as amitriptyline or mexiletine
e) NMDA antagonists for example ketamine or dextrometorfan
f) sodium channel blocking agents for example lidocaine
g) anticonvulsants, for example carbamazepine or lamotrigine
h) cannabinoids
A further aspect of the invention is new intermediate compounds which are useful in the synthesis of compounds according to the invention.
Thus, the invention includes
(a) a compound of the formula XI 
wherein Ar, R1-R4 and X are as defined for Formula I, L is bromide, iodide, or triflate and R1 may also be a nitrogen protecting group, such as a alkoxycarbonyl or a benzyl group, of which t-butoxycarbonyl is especially preferred and X, when containing, a nitrogen atom, may optionally be substituted with a t-butoxycarbonyl group.